Dr. Christopher Newton-Cheh is a cardiologist at the Massachusetts General Hospital and Instructor in Medicine at Harvard Medical School. The candidate's long-term goal is to develop an independent career as a genetic epidemiologist defining the contribution of genetics to common cardiovascular disease. As a fellow at the Broad Institute of Harvard and MIT (Bl) and the Framingham Heart Study (FHS), the candidate has studied the genetic determinants of electrocardiographic QT interval variation in an effort to better understand myocardial repolarization in the general population and to identify potential genetic risk factors for sudden death and drug-induced torsade de pointes. The proposed career development plan involves a well-defined mentored patient-oriented research proposal to extend these studies, in concert with a structured didactic curriculum of advanced statistical, epidemiologic and genetic coursework. Under the mentorship of Dr. Joel Hirschhorn and Dr. Christopher O'Donnell, Dr. Newton-Cheh has made significant progress defining the common genetic variation in several candidate genes associated with the congenital Long QT Syndrome. The proposed projects will achieve the following specific aims: 1) to complete candidate gene association studies of QT interval variation in 1811 FHS subjects, 2) to determine whether rarer variants identified by resequencing candidate genes in FHS subjects contribute to extreme QT interval prolongation and 3) to carry out genome-wide association studies of QT interval duration using 220,000 single nucleotide polymorphisms being genotyped in 2000 members of a South Pacific population isolate through an existing collaboration with investigators at Rockefeller University. These studies will provide the most comprehensive assessment of the genetic determination of myocardial repolarization in the general population to date. Through the proposed research and educational training, Dr. Newton-Cheh will acquire the skills needed to pursue independent cardiovascular research at the cutting edge of genomic science.